RNA sequencing of 13 T-cell acute lymphoblastic leukemia patients (5 TCRAD-MYC translocated T-ALL_8TAL1-LMO2 T-ALL)
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE106699 | GEO | 2018/07/01
REPOSITORIES: GEO
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Project description:Aberrant co-expression of LMO2 and TAL1 is regularly found in T cell acute lymphoblastic leukemia (T-ALL). Here we describe a xenotransplant model for primary T-ALL cells derived from a patient who developed LMO2/TAL1 associated T-ALL after gene therapy for X-SCID (gamma c deficiency) due to insertional activation and a SIL-TAL1 fusion as an additional independent event. We identified a protein complex containing LMO2, TAL1 and E47 in the patient’s T-ALL cells. This complex functions as a transcription regulation complex in undifferentiated hematopoietic cells. However, its role in T-ALL is not fully understood. By comparative gene expression profiling we identified retinaldehyde dehydrogenase (RALDH2) as one of the genes which was highly up regulated in the primary T-ALL cells; the gene product was N-terminally truncated (RALDH2-T), but enzymatically active. To investigate the interference of LMO2 in RALDH2-T expression as well as the role of RALDH2-T in T-ALL development, LMO1 (analogue of LMO2) was down regulated by RNA interference in the T-ALL cell line Jurkat which led to a decrease of RALDH2-T expression and cell viability, indicating that positive regulation of RALDH2-T through an LMO1 or 2 containing transcription regulation complex might be essential for maintaining the T-ALL phenotype. Keywords: Primary human T-ALL cells and CD8 cells of normal donors
2008-12-27 | GSE6920 | GEO
Project description:We differentiated WT, LMO2KO or TAL1 KO mouse ES cell lines into Flk-1+ haemangioblasts and/or Tie2+;Kit+;CD41- haemogenic endothelium 1 (HE1). We performed RNAseq, ChIPseq and/or DHS seq on these cells and compared the samples. Our study showed that Lmo2-/- embryonic stem cells differentiated less efficiently to haemogenic endothelium, which only produced primitive haematopoietic progenitors. LMO2 was required at the haemangioblast stage to position the TAL1/LMO2/LDB1 complex to regulatory elements that are important for the establishment of the haematopoietic developmental program. In the absence of LMO2, TAL1 protein levels were low and the target site recognition of TAL1 was impaired.
2017-11-01 | GSE99938 | GEO
Project description:RNA sequencing of 13 T-cell acute lymphoblastic leukemia patients (5 TCRAD-MYC translocated T-ALL_8TAL1-LMO2 T-ALL)
| PRJNA417699 | ENA
Project description:T-cell acute lymphoblastic leukemia (T-ALL) is mostly characterized by specific chromosomal abnormalities, some occurring in a mutually exclusive manner possibly delineating specific T-ALL subgroups. One subgroup, including MLL-rearranged, CALM-AF10 or inv(7)(p15q34) cases, is characterized by elevated expression of HOXA genes. Using a gene expression based clustering analysis of 67 T-ALL cases with recurrent molecular genetic abnormalities and 25 samples lacking apparent aberrations, we identified 5 new cases with elevated HOXA levels. Using array-CGH, a cryptic and recurrent deletion, del(9)(q34.11q34.13), was exclusively identified in 3 of these 5 cases. This deletion results in a conserved SET-NUP214 fusion product, that was also identified in the T-ALL cell line LOUCY. SET-NUP214 binds in the promoter regions of specific HOXA genes, where it may interact with CRM1 and DOT1L leading to the transcriptional activation of HOXA genes. Targeted inhibition of SET-NUP214 by siRNA abolished expression of HOXA genes, inhibited proliferation and induced differentiation in LOUCY but not in other T-ALL lines. We conclude that SET-NUP214 may contribute to the pathogenesis of T-ALL by enforcing T-cell differentiation arrest. We combined gene expression profiling and array-CGH analysis to detect a new and recurrent molecular cytogenetic abnormality in T-ALL patients that co-clustered with 5 well-defined HOXA-activated T-ALL samples. We describe the cloning of a recurrent SET-NUP214 fusion product in these samples, and identified a potential mechanism by which SET-NUP214 may activate the HOXA gene cluster as potential leukemogenic event in T-ALL. Experiment Overall Design: For 67 T-ALL patients having one of the major molecular cytogenetic abnormalities (i.e. TAL1 (n=24), LMO2 (n=9), HOXA (n=5), HOX11/TLX1 (n=7), and HOX11L2/TLX3 (n=22)), differentially expressed probesets were calculated from Affymetrix U133plus2.0 data based upon a Wilcoxon analysis and corrected for multiple testing for each probeset. Significant and differentially expressed probesets were obtained for the TAL1, HOX11 and HOX11L2 subgroups. No significant probesets were obtained for the HOXA subgroup or the LMO2 subgroup . As TAL1 and LMO2 both participate in the same transcriptional complex, activation of these genes may both lead to a highly similar expression profile. Combined analysis of TAL1 and LMO2 rearranged cases revealed significant and differentially expressed probesets that, as expected, almost entirely overlapped with the gene signature obtained for the TAL1-subgroup only. Next, we clustered 92 T-ALL cases, that besides the 67 cases as described above further included 25 T-ALL that lacked any of these recurrent abnormalities. Cluster analysis was performed based upon the top 25, 50 or 100 most significant probesets for the TAL1, TAL1/LMO2, HOX11 and HOX11L2 subgroups combined with 15 HOXA probesets identified by Soulier et al (2005)
2008-04-07 | E-GEOD-10609 | biostudies-arrayexpress
Project description:LMO2 regulates gene expression facilitating the formation of multipartite DNA-binding complexes. In B cells, LMO2 is specifically up-regulated in the Germinal Center (GC) reaction and is expressed in GC-derived non-Hodgkin’s lymphomas. LMO2 is one of the most powerful prognostic indicators in DLBCL patients. However, its function in GC B cells and DLBCL is currently unknown. In the present study we characterized the LMO2 transcriptome and interactome in DLBCL cells. LMO2 regulates genes implicated in kinetochore function, chromosome assembly and mitosis. Overexpression of LMO2 in DLBCL cell lines results in centrosome amplification. In DLBCL, the LMO2 complex contains some of the traditional partners such as LDB1, E2A, HEB, Lyl1, ETO2 and SP1, but not TAL1 or GATA proteins. Furthermore, we identified novel LMO2 interacting partners: ELK1, NFATc1 and LEF-1 proteins. Reporter assays revealed that LMO2 increases transcriptional activity of NFATc1 and decreases transcriptional activity of LEF-1 proteins. Overall, our studies identified a novel LMO2 transcriptome and interactome in DLBCL and provide a platform for future elucidation of LMO2 function in GC B-cells and DLBCL pathogenesis. RCK8 DLBCL cell lines were stably transfected with control plasmid or plasmid+LMO2
2012-07-12 | E-GEOD-34576 | biostudies-arrayexpress
Project description:LMO2 regulates gene expression facilitating the formation of multipartite DNA-binding complexes. In B cells, LMO2 is specifically up-regulated in the Germinal Center (GC) reaction and is expressed in GC-derived non-Hodgkin’s lymphomas. LMO2 is one of the most powerful prognostic indicators in DLBCL patients. However, its function in GC B cells and DLBCL is currently unknown. In the present study we characterized the LMO2 transcriptome and interactome in DLBCL cells. LMO2 regulates genes implicated in kinetochore function, chromosome assembly and mitosis. Overexpression of LMO2 in DLBCL cell lines results in centrosome amplification. In DLBCL, the LMO2 complex contains some of the traditional partners such as LDB1, E2A, HEB, Lyl1, ETO2 and SP1, but not TAL1 or GATA proteins. Furthermore, we identified novel LMO2 interacting partners: ELK1, NFATc1 and LEF-1 proteins. Reporter assays revealed that LMO2 increases transcriptional activity of NFATc1 and decreases transcriptional activity of LEF-1 proteins. Overall, our studies identified a novel LMO2 transcriptome and interactome in DLBCL and provide a platform for future elucidation of LMO2 function in GC B-cells and DLBCL pathogenesis.
2012-07-13 | GSE34576 | GEO
Project description:Relapse in T-cell acute lymphoblastic leukemia (T-ALL) may signify the persistence of leukemia-initiating cells (L-ICs). Ectopic TAL1/LMO expression defines the largest subset of T-ALL, but its role in leukemic transformation and its impact on relapse-driving L-ICs remain poorly understood. In TAL1/LMO mouse models, double negative-3 (DN3; CD4−CD8−CD25+CD44−) thymic progenitors harbored L-ICs. However, only a subset of DN3 leukemic cells exhibited L-IC activity, and studies linking L-ICs and chemotolerance are needed. To investigate L-IC heterogeneity, we used mouse models and applied single-cell RNA-sequencing and nucleosome labeling techniques in vivo. We identified a DN3 subpopulation with a cell cycle–restricted profile and heightened TAL1/LMO2 activity, that expressed genes associated with stemness and quiescence. This dormant DN3 subset progressively expanded throughout leukemogenesis, displaying intrinsic chemotolerance and enrichment in genes linked to minimal residual disease. Examination of TAL/LMO patient samples revealed a similar pattern in CD7+CD1a− thymic progenitors, previously recognized for their L-IC activity, demonstrating cell cycle restriction and chemotolerance. Our findings substantiate the emergence of dormant, chemotolerant L-ICs during leukemogenesis, and demonstrate that Tal1 and Lmo2 cooperate to promote DN3 quiescence during the transformation process. This study provides a deeper understanding of TAL1/LMO-induced T-ALL and its clinical implications in therapy failure.
2024-03-02 | GSE260697 | GEO
Project description:Relapse in T-cell acute lymphoblastic leukemia (T-ALL) may signify the persistence of leukemia-initiating cells (L-ICs). Ectopic TAL1/LMO expression defines the largest subset of T-ALL, but its role in leukemic transformation and its impact on relapse-driving L-ICs remain poorly understood. In TAL1/LMO mouse models, double negative-3 (DN3; CD4−CD8−CD25+CD44−) thymic progenitors harbored L-ICs. However, only a subset of DN3 leukemic cells exhibited L-IC activity, and studies linking L-ICs and chemotolerance are needed. To investigate L-IC heterogeneity, we used mouse models and applied single-cell RNA-sequencing and nucleosome labeling techniques in vivo. We identified a DN3 subpopulation with a cell cycle–restricted profile and heightened TAL1/LMO2 activity, that expressed genes associated with stemness and quiescence. This dormant DN3 subset progressively expanded throughout leukemogenesis, displaying intrinsic chemotolerance and enrichment in genes linked to minimal residual disease. Examination of TAL/LMO patient samples revealed a similar pattern in CD7+CD1a− thymic progenitors, previously recognized for their L-IC activity, demonstrating cell cycle restriction and chemotolerance. Our findings substantiate the emergence of dormant, chemotolerant L-ICs during leukemogenesis, and demonstrate that Tal1 and Lmo2 cooperate to promote DN3 quiescence during the transformation process. This study provides a deeper understanding of TAL1/LMO-induced T-ALL and its clinical implications in therapy failure.
2024-03-09 | GSE260948 | GEO
Project description:T-cell Acute Lymphoblastic Leukaemia (T-ALL) can be classified into a number of subfamilies, including those that overexpress TAL1/LMO, TLX1/3 and HOXA transcription factors. Whilst it has been previously shown in mouse models that TAL1/LMO transcription factors induce thymocyte self-renewal, whether this is the case for other transcription factor subclasses is currently unknown. To address this, we have studied vav-Nup98-HoxD13-transgenic (NHD13-Tg) mice, a model of HOXA-driven T-ALL, which overexpress HOXA transcription factors throughout haematopoiesis and display features of myelodysplastic syndrome in the bone marrow along with T-cell developmental abnormalities in the thymus and subsequent development of T-ALL in approximately 15% of mice. Thymocytes from preleukemic NHD13-Tg mice could engraft long-term in serial transplantation assays, demonstrating that NHD13-Tg thymocytes have acquired self-renewal capacity. Transcriptome analysis showed that NHD13-Tg thymocytes exhibited a Stem Cell like transcriptional program which closely resembled that of Lmo2 transgenic thymocytes, including Lmo2 itself and the critical Lmo2 cofactor Lyl1, suggesting a common mechanism of thymocyte self-renewal in these models. To determine whether Lmo2/Lyl1 are required for NHD13-induced thymocyte self-renewal, NHD13-Tg mice were crossed with Lyl1 knockout mice to generate NHD13-Tg mice lacking Lyl1. This showed that Lyl1 is essential for expression of the stem cell-like gene expression program in NHD13-Tg thymocytes and for thymocyte self-renewal. Surprisingly however, absence of Lyl1 accelerated the onset of T-ALL in NHD13-Tg mice. These studies demonstrate that Lyl1 is essential for self-renewal of NHD13-Tg thymocytes, suggesting that Lmo2 and Lyl1 may mediate thymocyte self-renewal induced by a variety of T-cell oncogenes. However, whilst Lyl1-induced thymocyte self-renewal is essential for Lmo2-driven T-cell leukemia, NHD13 can also promote T-ALL via an alternative pathway.
2019-03-04 | GSE121641 | GEO
Project description:LMO2 is an oncogenic transcription factor that is frequently overexpressed due to chromosomal abnormalities in T-cell acute lymphoblastic leukemia (T-ALL). In transgenic mouse models, Lmo2 overexpression causes thymocyte self-renewal resulting in T-cell leukemia with long latency. However, the requirement for Lmo2 for leukemia maintenance is poorly understood. To study this, we developed a Tetracycline-regulated knock-in mouse model that reversibly expresses Lmo2 throughout the haematopoietic system. This led to a specific impairment of T-cell development and the development of self-renewing preleukemic stem cells (pre-LSCs) in the thymus, followed by the development of fully penetrant T-lymphoblastic leukemia resembling human T-ALL. In preleukemic mice, repression of Lmo2 overcame the LMO2-induced thymocyte developmental block, reversed Lmo2-induced gene expression changes and eliminated self-renewing pre-LSCs in vivo. In contrast, overt T-lymphoblastic leukemias arising in this model were either immature, Lmo2-dependent leukemias resembling human ETP-ALL, or mature leukemias which were Lmo2-independent. Genomic analyses identified frequent loss of tumour suppressor genes in Lmo2-independent T-ALLs. Deletion of one of these, Ikaros (Ikzf1), was sufficient to transform Lmo2-dependent tumours to Lmo2-independence. Together these results indicate an evolution of oncogene addiction in T-ALL and that loss of Ikaros can promote self-renewal of T-ALL lymphoblasts in the absence of initiating oncogenes.
2020-12-31 | GSE144035 | GEO